Preparation for oral cavity

ABSTRACT

The present invention provides a preparation for attaching to teeth or tooth peripheries. The preparation for attaching to teeth or tooth peripheries of the present invention can give high adhesive force to the desired site despite interproximal space or curves of teeth. It is easy to hand while controlling drug release.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/069,325, filed on Jul. 11, 2018,which is a national phase entry under35 U.S.C. § 371 of International Application No. PCT/KR2017/000409,filed on Jan. 12, 2017, which claims priority to from Korean PatentApplication No. 10-2016-0012964 filed on Feb. 2, 2016, Korean PatentApplication No. 10-2016-0004353 filed on Jan. 13, 2016, and KoreanPatent Application No. 10-2016-0029820 filed on Mar. 11, 2016 in theRepublic of Korea, the disclosures of which are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to a mouth band which can be attached toteeth or tooth peripheries to deliver a medicinal ingredient into theoral cavity. More specifically, the present invention relates to a mouthband capable of effectively delivering the medicinal ingredient into theoral cavity by having excellent adhesive force and securing sufficientattachment time.

BACKGROUND OF THE INVENTION

In order to deliver an oral medicinal ingredient into the oral cavity,the contact time with a medicinal ingredient and the delivery amountplay an important role.

Paste formulations such as toothpaste have a disadvantage that it isdifficult to provide sufficient contact time at the target site due toinsufficient viscosity and high solubility, and mouth trays intended forintraoral drug delivery have a disadvantage that they have a strongsense of foreign body and difficult to deliver a drug locally due totheir shape characteristics. Patch type or strip type is thin, so it isdifficult to deliver sufficient amount of a medicinal ingredient, andflexibility is low, so there is a disadvantage that it is difficult tobe adhered to interproximal space, boundary area between gums and teeth,and the like.

In order to solve the adhesion problem to the interproximal space,boundary area between gums and teeth and the like, Korean PatentNo.10-0623859 developed a delivery system for a tooth whiteningcomponent using in situ gelling, but there was a disadvantage that it isnecessary to use a separate backing layer because it is highly flowablewhen applied to the tooth surfaces. Further, WO 2003/037276 discloses apreparation to be sprayed in the oral cavity due to its low initialviscosity, but there was a problem that the difference between thenormal storage temperature (especially in summer) and the temperature inthe oral cavity is small and it is difficult to remove it because thephase transition does not occur rapidly unless it is applied very thin.

U.S. Pat. No. 5,989,569 discloses about applying a drug to the surfaceof a strip and delivering the drug by pressure, but there were problemsthat the medicinal ingredient is temporarily released because the drugis applied on the surface of the strip and adhered to teeth as it is,and it may cause strong stimulus in the gums around the teeth. Further,there was a disadvantage that physical properties, in particular,flexibility, of the drug to be applied are different from those of thestrip, and therefore, adhesion to interproximal space is difficult.

The inventors of the present invention have studied for a long time todevelop a novel form of a preparation, which can effectively deliver adrug into the oral cavity with convenience of use, thereby completingthe present invention. In particular, the present inventors have beentrying to consider a formulation suitable for use under a specificcondition, i.e., in the oral cavity while improving adhesive force evento interproximal space or curves of teeth.

SUMMARY OF THE INVENTION

In order to solve the above problems, the present invention is directedto providing a novel form of a preparation for attaching to the oralcavity which is easy to be adhered to the desired site in the oralcavity and can secure sufficient contact time.

Further, the present invention is directed to providing a preparation inthe form that can be freely changed before use, and can be adhered wellto interproximal space or a boundary area between gums and teeth.

The present invention is directed to providing a novel form of apreparation, which can be excellently adhered not only to the buccalsurface or boundary area between gums and teeth but also tointerproximal space without flowing down at the beginning of attachment,and can be removed from teeth without any irritation at the time ofremoval after the drug is fully released.

The present invention is directed to providing a novel form of an oralpreparation, which is soft and flexible, and can be used convenientlybecause it does not flow down, and also can secure sufficient contacttime with the target site.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a preparation for attaching to teeth ortooth peripheries.

In one embodiment of the present invention, the preparation forattaching to teeth or tooth peripheries can be provides in the form ofmouth band.

The preparation for attaching to teeth or tooth peripheries according toone embodiment of the present invention is a shine hydrogel containingsynthetic; silica, and therefore it can be adhered in the oral cavity.

The term ‘mouth band’ used herein may mean a formulation that can beadhered to the teeth, gums, buccal and the like in the oral cavity. Forexample, it can be attached in the form of a band. The mouth band mayhave, for example, a rectangular shape, a round shape and the like, andmay be formed in various shapes in consideration of a target site,attachment time and the like. It may be provided in the form ofclay-like dough without any specific shape as needed.

The inventors of the present invention have studied for a formulation ofan oral preparation, which can easily transformed even by small pressureso as to deliver a drug up to interproximal space, and can have enoughadhesive force and shape retention force not to flow down from theattachment site, thereby completing the present invention.

The term ‘slime hydrogel’ used herein is used to mean hydrogel withexcellent elongation percentage and excellent stretchiness. Hydrogelforms a three-dimensional polymeric network and is swellable. Thehydrogel has the ability to absorb fluid and can release a drug at aconstant concentration, but it is stiff so that it is difficult to beadhered to curves or gaps of teeth and can be broken well when thehydrogel is stretched.

The slime hydrogel is excellent in malleability like jelly, stretcheswell, and has a three-dimensional polymeric network. Therefore, it is anovel formulation with excellent drug release control and free-shapetransformation.

In one embodiment of the present invention, the slime hydrogel may meana condition that is more resilient than a three-dimensional networkformed by hydrogen bonding of —OH groups of PVA and salts (for example,borate), and is shape-transformable. The slime hydrogel is a formulationthat is less flowable than slime and has more shape retention force, butis more flexible and stretchable than hydrogel. It may have moderateshape transformability between slime and hydrogel.

In one embodiment of the present invention, the slime hydrogelformulation may be achieved by synthetic silica or an alginate compound.

Silica is an inorganic thickener having very small and uniform size, andit is water-insoluble and excellent dispersion force in aqueoussolution. Although it was confirmed that the silica can be excellent inachieving slime hydrogel formulation because it has hydrogen bondingproperty thereby increasing thixotropic, the present invention is not tobe construed as limited to such theory.

The synthetic silica may be at least one selected from silica powder,fumed silica, precipitated silica, colloidal silica, aerogel and silicasol, and preferably it may be fumed silica. The fumed silica may be, forexample, AEROSIL® types from EVONIK such as AEROSIL® 200, AEROSIL®300and the like. The synthetic silica may be contained in an amount of 0.1wt % to 20 wt % based on the dry weight of the preparation for attachingto teeth or tooth peripheries, and it may be contained in an amount of0.5 wt % to 10 wt %.

Within the above content range, it may be preferred in terms of rheologyof the formulation.

In one embodiment of the present invention, the slime hydrogel may formhydrogen bonds by reacting polyvinyl alcohol (PVA) and —OH groups of thepolyvinyl alcohol. The polyvinyl alcohol is a polymer whose in vivostability is proven and is a film-forming polymer capable of forming athin film. The —OH group contained in the polyvinyl alcohol has anexcellent elastic property at the time of gel formation by a bridgestructure formed by hydrogen bonds with salts, and the desiredformulation property of the present invention can be achieved by the useof the synthetic silica of the present invention.

The salt forming hydrogen bonds with —OH groups of the polyvinyl alcoholmay be borate, phosphate or a mixture thereof, and the borate mayinclude potassium borate, sodium borate and the like, and the phosphatemay include tetrasodium pyrophosphate, tetrapotassium pyrophosphate andthe like.

Preferably, when considering compatibility between the PVA and thesynthetic silica, the salt may be sodium borate.

The preparation according to another embodiment of the present inventionmay be attached to the oral cavity as a slime hydrogel containing analginate compound.

It was confirmed that the hydrogen bonding property of the alginatecompound affects the formation of the slime hydrogel, and therefore, itcan exert an excellent effect in achieving the formulation giving thethixotropy property of the slime hydrogel. However, the presentinvention is not to be construed as limited to such theory. Preferably,the alginate compound may be contained in an amount of 0.1 wt % to 20 wt% based on the dry weight of the preparation, and the amount ofpreferably 5 wt % or less, more preferably 2 wt % or less, and mostpreferably 0.5 wt % or less is preferred because the slime hydrogel canbe formed uniformly within the range.

The alginate compound may include calcium alginate, potassium alginate,sodium alginate, triethanolamine alginate or a mixture thereof.

The preparation of the present invention may comprise a medicinalingredient which can be delivered into the oral cavity. The medicinalingredient may include all of the medicinal ingredients that can bedelivered into the oral cavity, and may preferably include a medicinalingredient intended to treat oral diseases or to prevent or improve oraldiseases and the like.

The medicinal ingredient may include, for example, an ingredient fortooth whitening, an ingredient for preventing cavity containing afluoride ion source, an ingredient for inhibiting tartar formation, ananti-inflammatory ingredient, an anti-bacterial ingredient, othervitamins, mineral ingredients and the like. Further, it may also includeingredients for improving sensitive teeth and for relieving itssymptoms, and the like. More specifically, for example, it may include:at least one fluoride ion source selected from the group consisting ofsodium fluoride, stannous fluoride, indium fluoride, amine fluoride andsodium monofluorophosphate; a remineralization agent containinghydroxyapatite; and an ingredient for tooth whitening selected fromhydrogen peroxide, carbamide peroxide, calcium peroxide, perborate,percarbonate, peroxyacid, persulfate, calcium chlorite, barium chlorite,magnesium chlorite, lithium chlorite, sodium chlorite or a mixturethereof. For enhancing whitening effect, a condensed phosphate can beused together with peroxides. The condensed phosphate, which can beused, may be at least one of tetrasodium pyrophosphate (TSPP), sodiumacid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodiumpotassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodiummetaphosphate and acidic sodium polyphosphate, and it may be usedtogether with peroxides. Such condensed phosphate also can be used forremoving tartar or inhibiting tartar formation. Further, it can alsocontribute to the improvement of whitening effect by removing the metalwhich affects the stain formation of teeth as a chelating agent. Themedicinal ingredient may include an anti-bacterial agent includingtriclosan, chlorhexidine, alexidine, hexetidine, sanguinarine,benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridiniumchloride (CPC), tetradecylpyridinium chloride (TPC) or a mixturethereof; an anti-inflammatory agent including aspirin, ketorolac,flurbiprofen, piroxicam, meclofenamic acid or a mixture thereof;thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine,biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A,vitamin D, vitamin E, vitamin K or a mixture thereof; or a mixturethereof, but not limited thereto. Further, the drug effective forpreventing and improving periodontal diseases may be titrated extract ofZea Mays L. unsaponifiable fraction, Magnoliae Cortex extract, Myrrha,Rhatany, Chamomile, policresulen, titrated extract of Centella Asiatica,nutmeg extract, dexpanthenol, β-sitosterol, acetyl salicylic acid andthe like alone, or a mixture thereof of a certain mixing ratio. Theingredient for improving and relieving sensitive teeth symptoms may bezinc chloride, potassium phosphate, potassium diphosphate, calciumchloride, oxalic acid, potassium oxalate, ferric oxalate, vitamin E andthe like alone, or a combination of two or more thereof.

The medicinal ingredient may be present as homogeneously orinhomogeneously dispersed in the slime hydrogel of the preparation.

The preparation according to one embodiment of the present invention mayfurther comprise a material, which can help release of the medicinalingredient dispersed in the slime hydrogel, and for example, thematerial for helping drug release may be any material that can form achannel, a porous structure or bubble (foam) in the formulation. Forexample, it may comprise any one selected from the group consisting ofi) acid such as acetic acid, lactic acid, malic acid, gluconic acid,ascorbic acid and the like or a water-soluble salt thereof, e.g., sodiumcitrate and ii) base such as sodium hydroxide (NaOH), potassiumhydroxide (KOH), sodium bicarbonate (baking soda) and sodium carbonate.Preferably, the acid may be acetic acid, and the base may be sodiumcarbonate, and more preferably, those may be sodium citrate and sodiumbicarbonate, which are an acid and a base mainly used in toothpaste.

The preparation according to one embodiment of the present invention maybe present as slime hydrogel itself, or may be present in the form inwhich a supporter (for example, a water-insoluble film) and the like arefurther attached. When it is attached to teeth or tooth peripheries, itmay further comprise a backing layer (backing film) as needed.

The backing layer may contact to an unwanted site while attaching thepreparation according to one embodiment of the present invention. Thus,the backing layer may serve to prevent the problem. The backing layermay include a water-insoluble polymer, generally used in an oral film,and for example, polyethylene (PE), polypropylene (PP), ethylene vinylacetate (EVA), cellulose acetate phthalate, shellac, polyvinyl acetate,ethyl cellulose, polymethyl methacrylate, methacryloylethylbetain/methacrylate copolymer (Yukaformer; Manufacturer: Mitsubishi),methacrylic acid copolymer (Eudragit L 100, Eudragit L 12,5, Eudragit L100-55, Eudragit L 30D-55), aminoalkyl methacrylate copolymer (EudragitE 100, Eudragit E 12,5, Eudragit RL 100, Eudragit RL 30D) and the likemay be used.

The term ‘tooth peripheries’ used herein is generally a conceptinvolving a region represented by gums, and may be used to meanincluding all of the mucosal regions around teeth. The tooth peripheriescan be used to mean covering the region where a medicinal ingredient forintra-oral delivery can be delivered together with the teeth when thepreparation is applied to the teeth in the structure of the preparation.Herein, ‘teeth or tooth peripheries’ is used together with ‘teeth’, andit may be understood herein to include both the teeth and the toothperipheries even if it is described only as ‘teeth’.

In one embodiment of the present invention, the preparation can beeasily removed from teeth at the time of removal after drug release iscompleted, and it may be removed with very little residue left on thesurface. In the case of containing the synthetic silica according to oneembodiment of the present invention, adhesive force to teeth may beincreased by mixing polyvinyl alcohol and sodium borate. Further, whenremoving the preparation after drug release is completed, it may beconveniently removed without leaving sticky on the tooth surfaces.

In another embodiment of the present invention, the present inventionprovides an oral preparation for attaching to teeth or tooth peripheriescomprising a phase transition compound and a polymer which is mixed withthe phase transition compound and can control hardening rate of thephase transition compound. The preparation may comprise a medicinalingredient which can be delivered into the oral cavity. After thepreparation is attached to teeth or tooth peripheries, the activeingredient contained in the preparation may be released and delivered tothe desired site in the oral cavity.

In general, in the case of a phase transition formulation, when thefirst formulation and the second formulation meet and phase transitionoccurs, it is present as a fixed mass. The inventors of the presentinvention have confirmed that when using the ingredient controllingphase transition rate used in the present invention together, a novelform of a preparation, which is effective to drug release by controllingthe hardening rate of the phase transition compound, can be provided,thereby completing the present invention.

The inventors of the present invention have studied for a long time todevelop a novel form of a preparation, which can effectively deliver adrug into the oral cavity with convenience of use, thereby completingthe present invention.

The conventional phase transition formulation generally forms a lumpafter completion of phase transition and then removed by peel-offmethod. When using the material of controlling phase transition rateaccording to one embodiment of the present invention together, theformulation may have a structure in which small lumps, rather than asingle lump, are united by weak bonds at the time of removal, andtherefore, it can be removed by brush-off method as if brushing with atooth brush. Namely, the present invention is characterized in that thepreparation of the present invention can be removed from the toothsurfaces through tooth brushing to give freshness in the oral cavityafter use.

The term ‘tooth peripheries’ used herein is generally a conceptinvolving a region represented by gums, and may be used to meanincluding all of the mucosal regions around teeth. The tooth peripheriescan be used to mean covering the region where a medicinal ingredient forintra-oral delivery can be delivered together with the teeth when thepreparation is applied to the teeth in the structure of the preparation.Herein, ‘teeth or tooth peripheries’ is used together with ‘teeth’, andit may be understood herein to include both the teeth and the toothperipheries even if it is described only as ‘teeth’.

The term ‘preparation’ used herein means to a product made by processingthe medicinal ingredient to secure its therapeutic effect withoutaffecting effectiveness of the medicinal ingredient.

Meaning of the term ‘applied to teeth’ used herein may include fromimmediately after locating the preparation of the present invention toteeth or tooth peripheries to before adhering the preparation to teethby applying pressure by a user.

The term ‘when adhering the preparation to teeth’ in the presentinvention means the time of adhering the preparation to curves of teeth,interproximal space, or the boundary between teeth and gums by applyingpressure after a certain period of time after application of thepreparation to teeth.

The term ‘time of removal of the preparation’ in the present inventionmay mean the time that the drug is released from the oral cavity afterit is adhered to teeth or tooth peripheries and then the preparation isremoved therefrom. Depending on the purpose and use of the preparation,and the release amount of the drug, but it may be removed after 2 hrfrom attachment, but it may be removed within 30 min, more preferablywithin 10 min after adhered to teeth in view of convenience of use.Hardness of the preparation at the time of removal may be increased,compared to the time at which the preparation is applied to teeth andthe time at which the preparation is adhered to teeth, and hardness ofthe preparation at the time of removal may be increased.

The term ‘controlling phase transition rate’ used herein can be used inthe same sense as controlling the hardening rate and hardening degree ofthe preparation, and means that the hardening degree of the preparationcan be controlled by phase transition with time.

The present inventors have studied on a drug delivery system capable ofdelivering a medicinal ingredient into the oral cavity, therebysuggesting a novel form of a drug delivery system and a novel method fordelivering the medicinal ingredient into the oral cavity using such asystem.

The present inventors have studied for a long time on a novel drugdelivery system capable of effectively delivering a medicinal ingredientto specific sites in the oral cavity (for example, sites requiring toothwhitening, site of generation of sensitive teeth, sites of oralinflammation, sites of periodontal disease, etc.). As a result, a novelform of an oral preparation, which can be conveniently applied to teethor a mucosal region in the oral cavity, and can be adhered well up to acurvy region and interproximal space so as to increase the drug reachrate at the desired site, has been developed.

Formulations, which are advantageous for delivering a drug up tointerproximal space, have generally been recognized as liquid or highlyflowable forms. However, the initial viscosity is so low that theformulations flow well and are not only inconvenient to use but alsohave a problem that sufficient contact time cannot be secured becausethe time to be adhered to the target site is short.

In order to solve this problem, the present inventors developed aformulation that is in a dough-like form and when it is attached toteeth or a target site in the oral cavity, it does not flow down wellwhile increasing initial adhesive force. Furthermore, the presentinventors confirmed that, in particular, when a polymer having strongadhesive property to gums and teeth in the oral cavity and having aproperty of being involved in phase transition mechanism is mixed with aphase transition compound, there is no large difference in viscositybetween the time of the initial use and the time of removal, andtherefore it can be easily attached and removed without any irritation,through tests, thereby developing a novel form of a preparation.

Meaning of the term ‘applied to teeth’ used may include from immediatelyafter locating the preparation of the present invention to teeth ortooth peripheries to before adhering the preparation to teeth byapplying pressure by a user.

The term ‘when adhering the preparation to teeth’ in the presentinvention means the time of adhering the preparation to curves of teeth,interproximal space, or the boundary between teeth and gums by applyingpressure after a certain period of time after application of thepreparation to teeth.

The term ‘time of removal of the preparation’ in the present inventionmay mean the time that the drug is released from the oral cavity afterit is adhered to teeth or tooth peripheries and then the preparation isremoved therefrom. Depending on the purpose and use of the preparation,and the release amount of the drug, but it may be removed after 2 hrfrom attachment, but it may be removed within 30 min, more preferablywithin 10 min after adhered to teeth in view of convenience of use.Hardness of the preparation at the time of removal may be increased,compared to the time at which the preparation is applied to teeth andthe time at which the preparation is adhered to teeth, and hardness ofthe preparation at the time of removal may be increased.

In one embodiment of the present invention, the preparation of thepresent invention may comprise a polymer of controlling hardening rateof the phase transition compound. The preparation according to oneembodiment of the present invention comprising the polymer ofcontrolling hardening rate of the phase transition compound may have lowinitial hardness that is convenient for use and may have relatively lowhardness at the time of removal after drug release is completed.Therefore, an oral preparation which can be easily removed and also lessirritating to the attachment site can be provided.

For example, among phase transition compounds, in the case of alginatepowder, when it is in contact with moisture, it hardens rapidly at thebeginning and the hardness is increased significantly with time.Therefore, release of the medicinal ingredient dispersed in thepreparation may not be smooth. However, in one embodiment of the presentinvention, a preparation prepared by mixing a polymer having a largenumber of carboxyl groups, which are the same reacting group asalginate, for example, PVM/MA (Gantrez) polymer is advantageous inreleasing a drug without experiencing rapid hardness change.

The term ‘hardness’ used herein may mean the amount of force required tocompress the preparation. Hardness of the preparation of the presentinvention is measured at compression test mode of Stable Micro System TAXT Plus. After filling 20 g of the preparation into a 50 mL beaker, a 20mm diameter aluminum probe for hardness measurement is set, and thenhardness is measured with test speed of 1.5 mm/s, distance as targetmode and distance of 10 mm. Hardness is understood as the peak value ofthe first cycle calculated. The unit can be expressed as g (g force).

The phase transition compound is a substance that causes viscousproperty to the oral composition. It may be carrageenan, pectin,xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassiumalginate, sodium alginate, lithium alginate, chitosan, poly-lactic acid(poly(D,L-lactic acid)), polylactide-co-glycolide(poly(DL-lactide-co-glycolide)), poly-caprolactone, polyacrylic acid(carbopol), polyvinylacetal diethyl aminoacetate (AEA),hydroxypropylmethyl cellulose, poly(methacrylic acid)-poly(ethyleneglycol), poly(D,L-lactide)-block-poly(ethyleneglycol)-block-poly(D,L-lactide), PEG-oligoglycolyl-acrylate,poly(N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinylalcohol, polyvinyl acetate, glyceryl monooleate, glyceryl monolinoleate,glyceryl monoarachidonate, glyceryl monostearate and the like alone or acombination of two or more thereof. Any material that can be used as aphase transition compound in the art can be used and is not limited tothe above examples.

Preferably, the phase transition compound may be ammonium alginate,magnesium alginate, potassium alginate, sodium alginate, lithiumalginate or a mixture thereof.

The phase transition compound may be contained in the preparationtogether with a polymer having a property of controlling hardening rateof the phase transition compound. The polymer having a property ofcontrolling hardening rate of the phase transition compound may have thesame functional group (for example, carboxyl group) as the functionalgroup contained in the phase transition compound.

The polymer having a property of controlling hardening rate of the phasetransition compound contained in the preparation of the presentinvention may comprise at least one selected from polymers having afunctional group involved in the phase transition mechanism of the phasetransition compound such as carboxyl group, hydroxyl group and the like.For example, when the preparation of one embodiment of the presentinvention is subjected to phase transition reaction by alginic acid anda salt thereof, the polymer may be a polymer having a carboxyl group,for example, at least one polymer selected from the group consisting ofpolyacrylic acid, sodium polyacrylate, carbomer, carbopol, acrylatecopolymer (Eudragit L-100), polyquarternium-39 and a copolymer of methylvinyl ether and maleic anhydride (PVM/MA copolymer). Preferably, thepolymer may be Gantrez that is one of copolymers of methyl vinyl etherand maleic anhydride, and most preferably, it may be Gantrez S-97 thatis water-soluble and in a grade applicable to oral products. The polymermay be preferably used for the purpose of the present invention due toits excellent adhesive force to teeth and gums. On the contrary, whenthe preparation is subjected to phase transition reaction by polyvinylalcohol, a polymer having a hydroxyl group, for example, at least onepolymer selected from the group consisting of polyethylene glycol,hyaluronate, microcrystalline cellulose, hydroxypropyl methyl cellulose,methyl cellulose, alginic acid and carrageenan.

Although the polymer having a property of controlling hardening rate ofthe phase transition compound is believed to interfere with the bindingof the phase transition compound to water-soluble calcium, and acarboxyl group (—COOH) contained therein interferes with the hardeningof the phase transition compound by binding to the water-solublecalcium, the present invention is not to be construed as limited to suchtheory

Preferably, the polymer having a property of controlling hardening rateof the phase transition compound may be water-soluble and also containthe same functional group as the functional group contained in the phasetransition compound. For example, the —COOH group contained in PVM/MAbinds to water-soluble calcium and interferes with the binding ofalginate to the water-soluble calcium, thereby delaying hardening.

The polymer having a property of controlling phase transition reactionrate may be contained in an amount of 0.01 wt % to 10 wt % based on thetotal weight of the preparation, and preferably it may be contained inan amount of 0.05 wt % to 5 wt %. When it is in contact with waterwithin the above range, the present invention can have the desiredhardness range and can provide excellent adhesive force. Further, whenthe content ratio of the polymer exceeds the above range, the bindingwith the phase transition compound is strong enough to affect therelease of the dispersed medicinal ingredient and inhibit the release ofthe medicinal ingredient. The phase transition compound and the polymerhaving a property of controlling phase transition reaction rate may bemixed at a weight ratio of 5:0.01 to 0.07, preferably 5:0.03 to 0.05(phase transition compound: polymer having a property of controllingphase transition reaction rate). When the weight ratio is within theabove weight ratio range, the desired hardness of the preparation can beachieved.

The medicinal ingredient can be homogeneously dispersed in the oralcomposition, and the case that the ingredient is inhomogeneouslydispersed is also included in the mixing of the present invention.

According to one embodiment of the present invention, the preparation ofthe present invention has semi-solid property at the same time, so thatit can be adhered to curves or gap.

The preparation of the present invention may have a form such as doughor clay, and it can be applied to teeth or tooth peripheries as the formof an ointment.

In one embodiment of the present invention, the preparation may be usedas two-formulation type, and as needed, it may be used asthree-formulation type. For example, i) the first formulation containinga phase transition compound; and the second formulation containing apolymer of controlling phase transition reaction rate, water, amedicinal ingredient and other ingredients which can be contained in apreparation may be mixed, and ii) the first formulation containing aphase transition compound; the second formulation containing a polymerof controlling phase transition reaction rate; and the third formulationcontaining water, a medicinal ingredient and other ingredients which canbe contained in a preparation may be mixed.

The first formulation and the second formulation or the firstformulation, the second formulation and the third formulation may bemixed and then applied to teeth or tooth peripheries.

According to another embodiment of the present invention, the presentinvention provides a preparation for attaching to teeth or toothperipheries, which comprises: a phase transition compound; and a polymerwhich makes hardness of the preparation after 1 min from mixing with thephase transition compound 140 g to 350 g and makes hardness of thepreparation after 10 min from the mixing with the phase transitioncompound 5,200 g to 13,000 g, and delivers the medicinal ingredientcontained in the preparation into the oral cavity.

The phase transition compound may be any substance causing viscousproperty that is included herein without limitation, and preferably, itmay be carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate,magnesium alginate, potassium alginate, sodium alginate, lithiumalginate, chitosan, poly-lactic acid (poly(D,L-lactic acid)),polylactide-co-glycolide (poly(DL-lactide-co-glycolide)),poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethylaminoacetate (AEA), hydroxypropylmethyl cellulose, poly(methacrylicacid)-poly(ethylene glycol), poly(D,L-lactide)-block-poly(ethyleneglycol)-block-poly(D,L-lactide), PEG-oligoglycolyl-acrylate,poly(N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinylalcohol, polyvinyl acetate, glyceryl monooleate, glyceryl monolinoleate,glyceryl monoarachidonate, glyceryl monostearate and the like alone or acombination of two or more thereof. Any material that can be used as aphase transition compound in the art can be used and is not limited tothe above examples. Preferably, the phase transition compound may bealginic acid or its salts, and preferably, the alginic acid or its saltsmay be ammonium alginate, magnesium alginate, potassium alginate, sodiumalginate, lithium alginate or a mixture thereof.

For effective release of the medicinal ingredient contained in thepreparation which comprises the phase transition compound and foreffective adhesion to teeth, interproximal space or tooth peripheries,the preparation should have enough viscous property and hardness foreasy handling of the preparation during 1 min after mixing the firstformulation and the second formulation, and preferably, hardness of 140g to 350 g may be good for easy handling. And after 10 min from themixing of the ingredients of the preparation, the drug release may occursmoothly, and hardness of 5,200 g to 13,000 g may be good formaintaining shape fixing force and adhesive force. In order to providethe hardness of the preparation intended in the present invention, thepreparation may preferably comprise at least one selected from the groupconsisting of polyacrylic acid, sodium polyacrylate, carbomer, carbopol,acrylate copolymer(Eudragit L-100), polyquarternium-39 and copolymer ofcopolymer of methyl vinyl ether and maleic anhydride (PVM/MA copolymer).Preferably, the polymer may be copolymer of methyl vinyl ether andmaleic anhydride (PVM/MA copolymer).

The shape fixing force which can be achieved by the preparation of thepresent invention can secure sufficient contact time with the site wherea drug is required to reach, and therefore, it may be more advantageousin achieving the desired effect.

The preparation according to one embodiment of the present invention mayhave difference between the hardness measured after 1 min from themixing and the hardness measured after 10 min from the mixing may be5,000 g to 12,000 g, preferably 6,000 g to 10,000 g. When the hardnessdifference is within the above range, attachment and handling may beeasy, and also drug release may be effective and removal may be easy.Therefore, it may be more advantageous in achieving the purpose of thepresent invention.

The preparation of the present invention may further comprise a materialfor helping drug release. The material for helping drug release may beany material that can form a channel, a porous structure or bubble(foam) in the formulation. For example, in the case that the preparationis consisting of two formulations of the first formulation and thesecond formulation, one formulation contains an acid and the othercontains a base, so that bubbles are formed in the formulation when thetwo formulations meet to form a viscous form. Namely, the firstformulation contains acetic acid, lactic acid, malic acid, gluconicacid, ascorbic acid and the like or a water-soluble salt thereof, e.g.,sodium citrate, and the second formulation contains at least one baseselected from the group consisting of sodium hydroxide (NaOH), potassiumhydroxide (KOH), sodium bicarbonate (baking soda) and sodium carbonate.Preferably, the acid may be acetic acid, and the base may be sodiumcarbonate, and more preferably, those may be sodium citrate and sodiumbicarbonate, which are an acid and a base mainly used in a toothpaste.

The hardness of the preparation of the present invention is graduallyincreased as the phase transition compound comes into contact withmoisture by mixing the first formulation and the second formulation.Therefore, it is easy to be attached to teeth and may not cause anyirritation to teeth or gums at the time of removal because it has lowerhardness at the time of removal than the hardness range at the time thata typical phase transition compound and water meet and has shape fixingforce.

The preparation for attaching to teeth or tooth peripheries provided inanother embodiment of the present invention comprises: i) a medicinalingredient, ii) a phase transition compound, and iii) a polymer that iswater-insoluble but ethanol-soluble. The preparation of the presentinvention is applied in liquid to teeth or tooth peripheries, and thenphase transited by contacting with saliva in the oral cavity, therebyhaving adhesiveness to teeth or tooth peripheries. Therefore, it mayhave adhesive property to teeth or tooth peripheries.

Ethanol is used as a solvent for manufacturing the preparation. Thepreparation of the present invention contains a polymer that is notdissolved in water at all or dissolved in water only in a certaincondition (for example, at a certain ratio of water and ethanol (forexample, ethanol is contained in an amount of 80% or more in a mixtureof water and ethanol) or at a certain pH condition), but dissolved inethanol. The preparation may contain a polymer that is water-insolublebut ethanol-soluble. The polymer that is water-insoluble butethanol-soluble may include a polymer that is not dissolved in water butdissolved in ethanol in conditions of a temperature of 35° C. to 38° C.,pH 7.

The preparation may provide excellent spreadability when applied toteeth or tooth peripheries, and may have adhesive property to teeth ortooth peripheries after a certain period of time in the oral cavity.

The inventors of the present invention confirmed through tests that theingredients contained in the preparation induce phase transition bycontacting with saliva, and at the same time, a polymer that iswater-insoluble but ethanol-soluble is used together, so that even if alarge amount of the preparation is loaded and thickly applied to thetarget site, the preparation can quickly harden and may have adhesiveproperty for enough time.

Solubility of the preparation of the present invention is changed in thehumid oral cavity. Namely, the preparation is dissolved in ethanol,which is a solvent of the preparation, and the solubility is reducedwhile being in contact with a large amount of water (saliva) having pHof 7 or lower in the oral cavity, and can remain at the target site forenough time to achieve the desired effect.

The preparation of the present invention is in the form of liquid havingexcellent flowability immediately after application in the oral cavity,and can penetrate well into the interproximal space and the boundarybetween teeth/gums. The preparation of the present invention reacts withsaliva over time after application, so that the preparation hardensgradually and goes through gelation. Therefore, the preparation can beattached to teeth or tooth peripheries.

The term “gelation” does not only include the phenomenon that the solchanges into gel, but also includes phenomenon accompanied by apronounced increase in elasticity or viscosity of the system. Itincludes a phenomenon in which the liquid phase gradually solidifies incontact with saliva, and there is no particular limitation on the degreeto which the elasticity or viscosity is increased by gelation.

The phase transition compound may include any one monoglyceride selectedfrom glyceryl monooleate, glyceryl monolinoleate, glycerylmonoarachidonate, glyceryl monostearate or a mixture thereof, andpreferably, it may be glyceryl monooleate and/or glyceryl monolinoleate.

The phase transition compound is preferably glyceryl monooleate for thepurpose of the present invention to induce phase transition in contactwith moisture. The phase transition compound can be contained in anamount of 5 wt % to 80 wt % based on the total weight of thepreparation. It is preferable for the purpose of the present inventionto have a feature of phase transition upon contact with a small amountof water or saliva in the above content range.

The preparation of the present invention uses a polymer that isdissolved only in ethanol and hardly dissolved in water together, andthe polymer dissolved only in ethanol is also converted from solublephase into insoluble phase upon contact with water. Therefore, since thepolymer dissolved only in ethanol goes through phase transition in adifferent sense, the phase transition compound may be included in thepreparation in such a content range.

The polymer that is water-insoluble but ethanol-soluble, contained inone embodiment of the present invention, may include a) a polymer thatis dissolved in ethanol but not dissolved in water, or b) a polymer thatis dissolved in ethanol but not normally dissolved in water butdissolved in water in a certain condition such as pH higher than the pHin the oral cavity (pH 7), for example a typical enteric coatingpolymers that is not dissolved in the stomach which is an acidiccondition, in the formulation which is a neutral condition but dissolvedonly in the intestine which is a basic condition. For example, b) thepolymer that is not normally dissolved in water but dissolved in waterin a certain condition such as pH higher than the general pH in the oralcavity (pH 7) may include a polymer that is dissolved in ethanol but notdissolved in water having pH of 7 or lower.

Monoglyceride is characterized in that it is phase transited dependingon the temperature and moisture content, and has a characteristic ofchanging the structural form and physical properties as the phasechanges. When the monoglyceride shows phase transition, it is convertedfrom the structure having fluidity into the structure having adhesiveproperty without fluidity. However, because the monoglyceride should beapplied thickly to make fast phase transition, it was characterized thatthe monoglyceride is applied to the desired target as a spray type asthin as possible. The phase transition preparation using themonoglyceride was too thin to be sufficient for delivery of a sufficientamount of a drug, and only partially used in preparations that did notrequire drug delivery with sufficient attachment time, such as some badbreath removers.

The present invention solves these problems and suggests a method foreffectively delivering a drug while securing sufficient attachment time.

The polymer that is water-insoluble but ethanol-soluble may be ethylcellulose, butyl ester of PVM/MA copolymer, polyvinyl acetate, polyvinylacetate-phthalate, shellac, rosin, methacrylic acid copolymer (forexample, EUDRAGIT® L100, L100-55) or a mixture thereof, and preferably,it may be ethyl cellulose, butyl ester of PVM/MA copolymer or a mixturethereof.

In one embodiment of the present invention, in particular, the medicinalingredient may preferably be a medicinal ingredient that is notdissolved in water well but dissolved only in ethanol. In anotherembodiment, the medicinal ingredient may preferably be a medicinalingredient that is not dissolved in water well but homogeneouslydispersed in water.

The preparation according to another embodiment of the present inventionmay typically have viscous property similar to viscous property of theflowing solution or gel, and for example, it may have viscous propertyof 10,000 or less, preferably 5,000 or less, more preferably 100 to10,000, most preferably 500 to 5,000 when measured at room temperatureby Brookfield Viscometer with RV6 spindle at speed 20. Through Examples,the present invention provides a preparation for attaching to teeth ortooth peripheries, which has the viscosity of the above range beforecontacting with saliva, but is phase transited to gel or solid havingadhesive property to teeth or oral tissues after applied to teeth or inthe oral cavity. The phase transition can be measured at an oraltemperature condition, preferably at a temperature of 36° C. to 38° C.

The viscous property can be obtained as a result of measuring theviscosity using Brookfield viscometer commonly used in the art at acondition of RV6 spindle at room temperature or oral temperature, andthe viscous property refers to a property having viscous property, andthe viscous property and the viscosity may be used interchangeably. Theunit may be expressed as cPs.

The preparation may comprise the polymer that is water-insoluble butethanol-soluble and the phase transition compound of the presentinvention.

In one embodiment, the preparation may comprise both of a polymerselected from glyceryl monooleate, glyceryl monolinoleate, glycerylmonoarachidonate, glyceryl monostearate or a mixture thereof; and apolymer selected from ethyl cellulose, butyl ester of PVM/MA copolymer,polyvinyl acetate, polyvinyl acetate-phthalate, shellac, rosin,methacrylic acid copolymer or a mixture thereof.

The term ‘tooth peripheries’ used herein is generally a conceptinvolving a region represented by gums, and may be used to meanincluding all of the mucosal regions around teeth. The surrounding partof teeth can be used to mean covering the region where a medicinalingredient for intra-oral delivery can be delivered together with theteeth when the preparation is applied to the teeth in the structure ofthe preparation. Herein, ‘teeth or tooth peripheries’ is used togetherwith ‘teeth’, and it may be understood herein to include both the teethand the tooth peripheries even if it is described only as ‘teeth.

The term ‘preparation’ used herein means to a product made by processingthe medicinal ingredient to secure its therapeutic effect withoutaffecting effectiveness of the medicinal ingredient.

The meaning ‘applied to teeth’ used herein may be included in themeaning of application when the preparation of the present invention isbrought into contact with teeth or a part of tooth peripheries.

The present inventors have studied on a drug delivery system capable ofdelivering a medicinal ingredient into the oral cavity, therebysuggesting a novel form of a drug delivery system and a novel method fordelivering the medicinal ingredient into the oral cavity using such asystem.

The preparation may further comprise a backing layer as required when itis attached to teeth or tooth peripheries. The preparation according toone embodiment of the present invention may be smeared to unwantedportions such as gums if the preparation hardens for a long time. Thus,the backing layer may also prevent the problem. The backing layer mayinclude a water-insoluble polymer, generally used in an oral film, andfor example, polyethylene (PE), polypropylene (PP), ethylene vinylacetate (EVA), cellulose acetate phthalate, shellac, polyvinyl acetate,ethyl cellulose, polymethyl methacrylate, methacryloylethylbetain/methacrylate copolymer (Yukaformer; Manufacturer: Mitsubishi),methacrylic acid copolymer (Eudragit L 100, Eudragit L 12,5, Eudragit L100-55, Eudragit L 30D-55), aminoalkyl methacrylate copolymer (EudragitE 100, Eudragit E 12,5, Eudragit RL 100, Eudragit RL 30D) and the likemay be used.

The preparation according to one embodiment of the present invention maybe easily removed by tooth brushing at the time of removal after drugrelease is completed.

According to one example of use, after applying the dough-typepreparation of the present invention on the backing layer, the bakinglayer is attached to the target site in the oral cavity, and then thebacking layer may be removed after a certain period of time (when thepreparation somewhat hardens and is not smeared to gums and the like).After removing the backing layer, the preparation of the presentinvention can be removed by tooth brushing with a tooth brush usuallyused at the time of removal. When used in a peel-off type, the backinglayer can be removed at the time of removal together with thepreparation without removing the backing layer in the middle of thehardening process.

For example, the preparation of the present invention can be removed bybrush-off (by tooth brushing) at the time of removal from teeth or toothperipheries after a certain period of time. The preparation of thepresent invention can be detached by external stimulation or pressuresuch as normal tooth brushing. A tool for brush-off may be, for example,a toothbrush, a sponge and the like, but the kind is not particularlylimited.

Advantageous Effects

The preparation of the present invention can give high adhesive force tothe desired site despite interproximal space or curves of teeth.

The preparation of the present invention can be easily removed withoutleaving stickiness on the tooth surfaces at the time of removal.

The preparation of the present invention is excellent in agglomeration,which can be self-healed like gum or dough. It is also easy to handlewhile controlling drug release.

The preparation is possible to sufficiently secure contact time betweenthe drug delivery site and the preparation of the present inventionbecause the preparation does not flow down or is not diluted with salivaafter attachment, and therefore, it is advantageous to achieve thedesired efficacy.

The preparation can be used conveniently because it does not flow downwhen applied to teeth.

The preparation has a relatively high hardness at the beginning ofattachment, so that it can be easily handled without flowing down, andit can be easily removed and may cause less irritation around theattached site due to its relatively small increase in hardness after acertain period of time from the attachment.

In general, oral preparations containing phase transition compoundsshould be applied to a thickness that is too thin to secure sufficientcontact time with the attachment site, but the present invention cansecure sufficient contact time because solubility of the preparation israpidly changed (soluble→insoluble) in the humid oral cavity even if thepreparation is applied thickly.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows PVM/MA that is an example of a polymer which can controlhardening rate of a phase transition compound according to the presentinvention (left), and illustrates structure of the formedalginate-calcium complex (right).

FIG. 2 shows hardness change checked after 1 min from mixing of thepreparation. The unit of the vertical axis is denoted by g. As can beseen from FIG. 2, it can be found that in the case of Examples, harnessis more rapidly increased from right after mixing the preparation toafter 1 min from the mixing, and after 1 min from the mixing, hardnessof Examples is higher than that of Comparative Examples. Namely, it canbe confirmed that after 1 min from the mixing, the preparations ofExamples are easier for users to handle than those of ComparativeExamples.

FIG. 3 show hardness change checked from just before mixing to after 10min from the mixing. As can be seen from FIG. 3, it can be found thatafter 10 min from mixing, hardness of the preparations of Examples islower than that of Comparative Examples. Namely, it can be found thatComparative Examples harden harder after a certain period of time fromthe attachment.

FIG. 4 is a drawing prefiguratively showing the process that thepreparation according to one embodiment of the present invention ishardening after applying and adhering the preparation to teeth. As canbe seen from FIG. 4, the preparation of the present invention can reachup to interproximal space.

T refers to teeth, and 10 refers to a preparation for attaching to teethor tooth peripheries.

DETAILED DESCRIPTION OF INVENTION

Hereinafter, the present invention will be described in more detailthrough the following embodiments. However, the embodiments according tothe present invention may be modified in many different forms, and thescope of the present invention shall not be construed as being limitedto the embodiments described below. The embodiments of the presentinvention are provided for illustration to help a full understanding ofthe present invention. Unless stated otherwise, % used herein isunderstood to mean wt %.

EXAMPLES

[Preparation of Mouth Band and Oral Preparation]

Examples and Comparative Examples were manufactured according to thefollowing method.

The preparations were manufactured according to the followingcomposition by adjusting to 50° C. and then mixing with a mechanicalmixer.

TABLE 1 Example 1 Example 2 Example 3 PVA 2.8% PVA 2.8% PVA 2.8%Magnoliae 0.05% Centella 0.02% Zinc 0.1% Cortex extract chloride extractethanol 1.0% TPP 10.0% ethanol 1.0% Borax 1.2% Aerosil200 1.2% Borax1.2% Aerosil200 2.4% Water to 100% Sodium 0.3% Water to 100% AlginateWater to 100%

TABLE 2 Comparative Example 4 Comparative Comparative Comparative (P&GExample 1 Example 2 Example 3 SensiStop ™) PVA 2.8% PVA 10% PVA 2.8%Cellulose Magnoliae 0.05% Centella 0.02% Zinc 0.1% Gum. Cortex extractchloride Carbomer, extract ethanol 1.0% TPP 10.0% NaOH, ethanol 1.0%Water to 100% Water to 100% Glycerin, Borax 1.2% Water Water to 100%

[Evaluation of Adhesive Force in Interproximal Space and Buccal Surface]

1. Test for Comparison of Interproximal Space and Buccal SurfaceAdhesive Force (Applying Method for Removing Artificial Dental Plaque)

(1) Test Method

-   -   Evaluation device: ITPlus 4.0 Microcam    -   Evaluation method: Before and after attachment of Comparative        Examples and Examples, rate for removing artificial dental        plaque on interproximal space and buccal surface was compared by        area

a) Method for Coating Artificial Dental Plaque on Artificial DentalModel

Among gnathostaic models, maxillary posterior buccal surface that iseasy to apply a troothbrush was inserted into a polymer (containing RedDye) for 10 sec. After removing it, it was dried at room temperature for60 min and then dried again in a drying room for 60 min to manufactureartificial dental plaque.

b) Test Method for Interproximal Space and Buccal Surface Adhesive Force

Examples and Comparative Examples were sprayed with a small amount ofwater to adjust the humid oral conditions and then adhered to theartificial dental plaque coated artificial teeth to be tested. Then, theartificial dental plaque on the interproximal space and the frontalsurface of the tooth was removed by removing the preparation after 10min under the same conditions, and then area of the interproximal spaceand the buccal surface was measured and compared.

(2) Test Result

The area of the artificial dental plaque removed from the interproximalspace and the frontal surface by the use of Example and ComparativeExample was measured. (The large area of plaque removal reflects thehigh adhesive force at that location)

TABLE 3 Comparative Comparative Area Example 1 Example 2 Example 1Example 4 Interproximal 30.01 28.90 25.80 10.55 space Buccal surface89.98 85.33 79.12 70.11

As can be seen from Table 3, Examples 1 and 2 showed large area ofplaque removal at both of the interproximal space and the buccalsurface. From the above result, it can be found that Examples 1 and 2have excellent ability to be adhered up to the interproximal space, andit also can be found that those have low flowability and can securesufficient contact time with the buccal surface, thereby havingexcellent ability to remove plaque from the buccal surface.

[Test for Comparison of Shape Retention Force and Length Extendibility]

1. Shape Retention Force

After attaching Example and Comparative Example to the dental modelconsisting of both the upper jaw and the lower jaw, the time at whichshape was not maintained and the preparation began to flow was recordedto evaluate whether there is physical strength to maintain the attachedshape during use time. Using the dental model, the preparation wasattached to the maxillary area to cover about three or more boundaryareas between gums and teeth. After 10 min, whether the preparationflows down to the mandibular area or maintains the attachment state wasobserved. Then, using 5-point scale, if the shape is maintained same asinitial stage, it is marked as 5 point, if the preparation slightlyflows down but the shape and the position are maintained, it is markedas 4 point, if the shape and the position are slightly off while flowingdown, it is marked as 3 point, if the shape and the position are muchoff, it is marked as 2 point, and if the shape and the position arecompletely off from the attachment site, it is marked as 1 point.

TABLE 4 Comp. Comp. Comp. Comp. Exam. Exam. Exam. Exam. Exam. Exam.Exam. 1 2 3 1 2 3 4 Shape 5 5 5 3 2 2 4 retention force

2. Test for Comparison of Stretchable and Malleable Properties

For Examples showed excellent shape retention force in Table 4, lengthextendibility was further tested.

1 g of Example was taken and placed on a PET sheet in the size of 1 cm*1cm, another PET sheet was placed thereon, and then the length that couldbe maximally extended without tearing or puncturing the sheet bypressing with a finger was measured and compared.

TABLE 5 Example 1 Example 2 Example 3 Comparative Example 4 Extended 6times 8 times 1.5 times Not extended when length pressed in productstate

As can be seen from Table 5, it can be found that Examples attached tothe tooth surfaces have excellent shape retention force and excellentlength extendibility, and therefore those have stretchablecharacteristic. In particular, Comparative Example 4 didn't showsignificant difference from Examples of the present invention in termsof shape retention force, but it had a characteristic in which thelength was not extended when pressed. Due to this difference, thepreparation of Comparative Example 4 was difficult to be completelyadhered up to the interproximal space. However, the preparation of thepresent invention was able to have perfect adhesive force inconsideration of curves or gaps of teeth.

[Survey for Convenience of use to Human Subject (Adhesive Force, ShapeRetention Force, Adhesive Force, Removability and the like)]

1) Test subject and instructions: A total of 10 volunteers were asked touse Examples 1 to 3 and Comparative Examples 1 to 4 alternately threetimes, respectively, and then survey was conducted using 5-point Likertscale.

2) Criteria

5: Very satisfied

4: Relatively satisfied

3: Moderate

2: Little unsatisfied

1: A lot unsatisfied

As guideline, if the preparation was easily attached to the desiredposition and stuck to the place for the desired time where it wasattached, the adhesive force was evaluated to be excellent, if thepreparation was attached to the desired position and then it maintainedthe shape well without flowing down, the shape retention force wasevaluated to be excellent, and if the preparation was easily adhered tothe interproximal space or the boundary between teeth and gums bylightly pressing it with a finger, the adhesive force was evaluated tobe excellent. Then, survey for removability was conducted according tothe following 5-point Likert scale.

5 : Removal is very convenient and there is no residue on teeth.

4 : Removal is convenient but there is little residue.

3 : Removal is inconvenient and there is inconvenience due to residue.

2 : Removal is inconvenient and there are many residues.

1 : Removal is very inconvenient and there are so many residues.

3) Test result

TABLE 6 Comp. Comp. Comp. Comp. Exam. Exam. Exam. Example ExampleExample Example 1 2 3 1 2 3 4 Adhesive 4 4 4 4 4 2 2 force Shape 5 5 5 32 2 4 retention force Adhesive 5 5 5 5 2 5 3 force Removability 5 5 5 42 4 2

As can be seen from Table 6, Examples were able to obtain very excellentresults overall in terms of adhesive force. Namely, the degree offlowing down after attachment was less than that of ComparativeExamples.

Further, Examples obtained good result in terms of adhesive force, butwhen considering the shape retention or adhesive force overall, Examplesobtained more excellent sense of use result.

[Survey for Clinical Sensitive Teeth or Gingivitis Relief to HumanSubject]

1) Test subject and instructions: Examples 1 to 3 and ComparativeExamples 1 to 4 were attached to sensitive teeth or gum pain area for 10min once a day and then removed.

2) For each group, 15 volunteers who experienced sensitive teeth or gumpain were asked to use for 1 week and then survey was conductedaccording 5-point Likert scale.

5: Sensitive teeth/gum pain relief effect lasted for one month in allattached sensitive teeth/gum pain areas.

4: Sensitive teeth/gum pain relief effect was definitely felt in allattached sensitive teeth/gum pain areas.

3: Sensitive teeth/gum pain relief effect was definitely felt in atleast one attached sensitive teeth/gum pain area.

2: Sensitive teeth against cold food or gum pain after eating becameless sensitive, compared to before use.

1: Sensitive teeth or gum pain relief effect was not felt.

The survey results of efficacy of Example and Comparative Example wereobtained as follows.

TABLE 7 Comp. Comp. Comp. Comp. Exam. Exam. Exam. Example ExampleExample Example 1 2 3 1 2 3 4 Sensitive — — 4 — — 3 3 teeth reliefGingivitis 4 4 — 3 1 — — relief

As can be seen from Table 7, mouth bands of Examples showed moreexcellent efficacy in the oral cavity than those of ComparativeExamples. Mouth bands of Examples had excellent adhesive force to thetarget site in the oral cavity and could deliver the drug up to theinterproximal space. Therefore, those are advantageous to achieve thedesired effect. Further, sufficient contact time could be secured andtherefore drug delivery was easy.

[Preparation of Oral Preparation]

Oral preparations of Examples and Comparative Examples having thefollowing composition were manufactured or purchased.

Examples and Comparative Examples were manufactured according to thefollowing method.

The preparations were manufactured according to the followingcomposition by adjusting the temperature of the second formulation to50° C. and then mixing with a mechanical mixer. The amount of thealginate powder mixed with the second formulation was 100 times to theweight of the second formulation.

TABLE 8 Example 4 Example 5 Example 6 First Alginate powder Alginatepowder Alginate powder formulation Second Zinc chloride 2.0% MagnoliaeCortex 0.1% Hydrogen peroxide 6.0% formulation (medicinal ingredient)extract (medicinal ingredient) PVM/MA 0.2% (medicinal ingredient) PVM/MA1.0% Water to 100% PVM/MA 0.35% Water to 100% Water to 100% ComparativeComparative Comparative Example 5 Example 6 Example 7 First Alginatepowder Alginate powder Alginate powder formulation Second Zinc chloride2.0% Magnoliae Cortex 0.1% Hydrogen peroxide 6.0% formulation (medicinalingredient) extract (medicinal ingredient) Water to 100% (medicinalingredient) HPMC 1.0% PVA 0.35% Water to 100% Water to 100%

[Hardness Comparison Test (Test Method: Measured by using TextureAnalyzer)]

Evaluation device: Stable Micro System TA XT Plus

Evaluation method: Hardness of Comparative Example and Example wasmeasured by using Texture Analyzer

Hardness was measured at compression test mode of TA (Texture Analyzer).After filling 20 g of Example and Comparative Example into a 50 mLbeaker, a 20 mm diameter aluminum probe for hardness measurement wasset, and then hardness was measured with test speed of 1.5 mm/s,distance as target mode and distance of 10 mm. The hardness calculatedfrom the device is the peak value of the first cycle.

Test result

The first formulations and the second formulations of Examples andComparative Examples listed in Table 8 were mixed and then the resultsof comparison of hardness with time were shown in the following Table 9.

TABLE 9 Comp. Comp. Comp. Example Example Example Example ExampleExample 4 5 6 5 6 7 1 min from 150 g 180 g 340 g 109 g 120 g 80 g mixing3 min 260 g 280 g 810 g 14,800 g 180 g 15,000 g 5 min 2,400 g 1600 g2,100 g 21700 g 5,000 g 20,000 g 10 min 12,000 g 5,600 g 5,400 g 22600 g16,000 g 22,400 g

As can be seen from Table 9, in the initial stage after mixing, thehardness values of Examples were higher and it was easy to apply toteeth or to be handled easily, and until 10 min after mixing, there wasno large hardness change, so it was convenient to remove and easy to usewithout any irritation. The results of graphically representing thehardness change according to Examples and Comparative Examples wereshown in FIG. 2 and FIG. 3.

[Test for Sense of use after Attachment]

Test for sense of use was carried out using the preparations having thecomposition according to Table 8. The first formulation and the secondformulation were mixed just before use, and then the mixture was appliedon a backing layer. The preparation was attached to the desired siteusing the backing layer and then pressed with a finger to be adhered. Itis not necessary to remove the backing layer, but in the test, thebacking layer was removed after 2 min from the attachment. After 10 minfrom the attachment, the preparation was removed.

1. Survey for Adhesive Force

30 Respondents were asked to use each of the preparations of ComparativeExamples 5 to 7 and Examples 4 to 6 depending on the group according tothe above instructions. Then, each group changed and used the productsand then responded to a questionnaire for adhesive force to gaps betweenteeth (interproximal space).

Criteria for Survey Response

5: Adhered well to gums and gaps between teeth by lightly pressing witha finger and easily removed

4: Adhered to gaps between teeth by lightly pressing with a finger butadhesive force to gums is moderate.

3: Adhered to gaps between teeth by lightly pressing with a finger butadhesive force to gums is weak.

2: Adhesive force to teeth is strong, but adhesive force to gaps betweenteeth is weak.

1: Adhesive force to teeth is strong, but adhesive force to gums isweak.

2. Survey for Removability

30 Respondents per group were asked to use each of the preparations ofComparative Examples 5 to 7 and Examples 4 to 6 according to the aboveinstructions. Then, each group changed and used the products and thenresponded to a questionnaire for removability.

Criteria for Survey Response

5: Removal is very convenient and there is no residue on teeth.

4: Removal is convenient but there is little residue.

3: Removal is inconvenient and there is inconvenience due to residue.

2: Removal is inconvenient and there are many residues.

1: Removal is very inconvenient and there are so many residues.

3. Survey for Clinical Sensitive Teeth or Gum Pain Relief to HumanSubject

1) Test subject and instructions: Example 5 and Comparative Example 1were attached to sensitive teeth or gum pain area for 10 min once a dayand then removed.

2) For each group, 15 volunteers who experienced sensitive teeth or gumpain were asked to use for 1 week and then survey was conductedaccording 5-point Likert scale.

3) Scale criteria

5: Sensitive teeth or gum pain relief effect lasted for one month in allattached sensitive teeth or gum pain areas.

4: Sensitive teeth or gum pain relief effect was definitely felt in allattached sensitive teeth or gum pain areas.

3: Sensitive teeth or gum pain relief effect was definitely felt in atleast one attached sensitive teeth or gum pain area.

2: Sensitive teeth against cold food was felt less sensitive, or gumpain was felt reduced, compared to before use.

1: Sensitive teeth or gum pain relief effect was not felt.

4. Survey for Feeling of Whitening Effect to Human Subject

1) Test subject and instructions: Examples 1 and 4 and ComparativeExample 2 were attached to six teeth in the middle of the upper teethfor 30 min or longer once a day and then removed.

2) For each group, 15 volunteers who felt the need for tooth whiteningbecause they usually thinks that their teeth are yellow were asked touse for 1 week. Then, survey for feeling of whitening effect, comparedto the unattached lower teeth, was conducted according 5-point Likertscale.

3) Scale criteria

5: Compared to the unattached lower teeth, felt a definite whiteningeffect than before use within 5 days.

4: Compared to the unattached lower teeth, felt that the teeth aredefinitely brighter than before use within 5 days.

3: Compared to the unattached lower teeth, felt that the teeth aredefinitely brighter than before use after 1 week use.

2: Compared to the unattached lower teeth, felt that the teeth areslightly brighter than before use.

1: Felt no difference, compared to before use.

5. Measurement Result

The following Table 10 shows removability and adhesive force ofComparative Examples and Examples, and sensitive teeth relieving effect,gingivitis relieving effect and degree of feeling of whitening werelisted in table.

TABLE 10 Comp. Comp. Comp. Exam. Exam. Exam. Exam. Exam. Exam. 4 5 6 5 67 Removability 5 5 5 5 5 5 (peel-off) (brush-off) (brush-off) (peel-off)(peel-off) (peel-off) Adhesive 5 5 5 5 5 5 force Sensitive 4 — — 2 — —teeth relieving effect Gingivitis — 5 — — 2 — relieving effect Feelingof — — 4 — — 1 whitening effect

[Drug Release Rate Comparison Test]

A) Manipulation

0.9% Sodium chloride solution 500 mL is poured in a test tube and atemperature of a test solution is maintained at 32±0.5° C. during drugrelease test. Example or Comparative Example as a sample is fixed on theupper side of a disk which can be used as a sinker without absorbing,interfering or reacting so that a target attachment surface facesoutward. Then, the disk is placed in the test tube with thesample-attached side facing up, and drug release time is calculated fromthis point of time. The sample-attached disk is aligned parallel to thebottom of the test tube and a paddle blade. Distance between the paddleblade and the sample surface is set to 25±2 mm, and revolutions per min(rpm) is set to 25. At the time of sampling, 100 mL of sample solutionis collected at a fixed position (a position 1 cm away from the wall ofthe test tube, between the top of the paddle blade and the test liquidsurface) 30 min after the start of the test. The drug release test wasconducted under a general laboratory condition, i.e., under a conditionof relative humidity of about 65%, 25° C.

B) Drug Analysis Method

Depending on the drug or the content, an appropriate analysis isselected. For example, peroxides are analyzed by titration, metal saltsare analyzed by ICP analysis, and natural extracts are analyzed by HPLC.

C) Result of Medicinal Ingredient Release Test

TABLE 11 Comp. Comp. Comp. Exam. Exam. Exam. Exam. Exam. Exam. 4 5 6 5 67 Time for 10 min 10 min 10 min Undetectable Undetectable Undetectablereleasing 70% or more of medicinal ingredient

As can be seen from Table 11, it was confirmed that Examples couldrelease about 70% of the medicinal ingredient at the time after 10 minfrom the attachment. However, in the case of Comparative Examples, drugrelease was not smooth due to rapidly increased hardness, and due tothis, the degree of drug release was undetectable.

[Preparation of Oral Preparation]

Oral preparations of Examples and Comparative Examples having thefollowing composition were manufactured or purchased.

TABLE 12 Example 7 Example 8 Example 9 Composition Vitamin E 0.1%Hydrogen peroxide 6% Oxalic acid 6% Magnoliae Cortex extract 0.05%Glyceryl monostearate 30% Glyceryl monolinoleate 40% Glyceryl monooleate41.5% Ethyl cellulose 10% Butyl ester of 8% Ethyl cellulose 8% ethanolto 100% PVM/MA copolymer(50%) ethanol to 100% ethanol to 100%Comparative Example 8 Comparative Example 9 Comparative Example 10Composition Vitamin E 0.1% Hydrogen peroxide 6% Oxalic acid 2% MagnoliaeCortex extract 0.05% Glyceryl monostearate 30% Butyl ester of 8%Glyceryl monooleate 41.5% Polyvinyl pyrrolidone 2% PVM/MA copolymer(50%)ethanol to 100% ethanol to 100% ethanol to 100%

Comparative Example 11: Parodontax™

Comparative Example 12: Median intensive whitening gel (polyvinylpyrrolidone, ethanol, water etc.)

Comparative Example 13: P&G Sensi Stop™

Examples and Comparative Examples of Table 12 were manufacturedaccording to the following method.

Ethanol solvent was heated to around 50° C. and then polymers weredissolved therein by stirring with a mechanical stirrer to aiddispersion and dissolution of the polymers at a constant rpm. Inparticular, the polymer that is contained in a large amount and takes along time to dissolve (for example, Glyceryl monooleate) was dissolvedfirst and then other polymers were dissolved. Then, other ingredientsand a medicinal ingredient were added thereto to make uniform solutionor gel.

<Evaluation of Dissolution Rate and Remaining Amount>

1. Evaluation of solubility in hot and humid oral condition without anyseparate physical force

In order to evaluate retention time in hot and humid oral condition, anartificial teeth made from a hydroxyapatite table (1 cm diameter) wasfixed with silicone molding, and then 0.5 g of each of Examples 7 to 9and Comparative Examples 8 to 12 was loaded thereon. Then, the time ofcomplete dissolution when immersed in a thermohygrostat of 37° C. and95% humidity was measured. A separate dissolution test was not carriedout to Comparative Example 13 in the form of a patch.

2. Evaluation of solubility in artificial saliva with applied physicalforce like flowing saliva

An artificial teeth made from a hydroxyapatite table (1 cm diameter) wasfixed with silicone molding, and then 1 g of each of Examples 7 to 9 andComparative Examples 8 to 12 was loaded thereon. Then, in order toevaluate retention time by saliva, the time of complete dissolution whenflowing the artificial saliva from top to bottom at a rate of 1 ml/minwas measured.

3. Test result

The results of evaluation of solubility in a hot and humid conditionwithout a separate physical force and the results of evaluation ofsolubility in artificial saliva in which physical force like flowingsaliva was applied were shown in the following Table 13.

TABLE 13 Comp. Comp. Comp. Comp. Comp. Complete dissolution Exam. Exam.Exam. Exam. Exam. Exam. Exam. Exam. (disintegration) time 7 8 9 8 9 1011 12 Left in condition of >30 min >30 min >30 min <6 min <5 min <5 min3 min 2 min 37° C., 95% Condition in which >30 min >30 min >30 min 15min 10 min 15 min 2 min 1 min artificial saliva flows at a rate of 1ml/min

As can be seen from Table 13, it was confirmed that Example was notcompletely dissolved even after 30 min. However, it was confirmed fromthe results that Comparative Example was easily and completelydissolved.

<Panel Evaluation>

1. Survey for Clinical Sensitive Teeth or Gum Pain Relief

1) Test subject and instructions: Examples 7 and 9 and ComparativeExamples 8 and 10 to 12 were applied or attached to sensitive teeth orgum pain area for 10 min once a day and then removed.

2) For each group, 15 volunteers who experienced sensitive teeth or gumpain were asked to use for 1 week and then survey was conductedaccording 5-point Likert scale.

3) Scale criteria

5: Pain relief effect lasted for one month in all sensitive teeth or gumpain areas where the product was applied.

4: Pain relief effect was definitely felt in all sensitive teeth or gumpain areas where the product was applied.

3: Pain relief effect was definitely felt in at least one sensitiveteeth or gum pain areas where the product was applied.

2: Sensitive teeth against cold food was felt less sensitive, or gumpain was felt reduced, compared to before use.

1: Sensitive teeth or gum pain relief effect was not felt.

2. Survey for Feeling of Whitening Effect to Human Subject

1) Test subject and instructions: Example 8 and Comparative Examples 9and 12 were attached to six teeth in the middle of the upper teeth for30 min or longer once a day and then removed.

2) For each group, 15 volunteers who felt the need for tooth whiteningbecause they usually thinks that their teeth are yellow were asked touse for 1 week. Then, survey for feeling of whitening effect, comparedto the unattached lower teeth, was conducted according 5-point Likertscale.

3) Scale criteria

5: Compared to the unattached lower teeth, felt a definite whiteningeffect than before use within 5 days.

4: Compared to the unattached lower teeth, felt that the teeth aredefinitely brighter than before use within 5 days.

3: Compared to the unattached lower teeth, felt that the teeth aredefinitely brighter than before use after 1 week use.

2: Compared to the unattached lower teeth, felt that the teeth areslightly brighter than before use.

1: Felt no difference, compared to before use

3. Evaluation Result

TABLE 14 Comp. Comp. Comp. Comp. Comp. Comp. Exam. Exam. Exam. Exam.Exam. Exam. Exam. Exam. Exam. 7 8 9 8 9 10 11 12 13 Sensitive teeth 5 33 improvement Whitening 4.5 3 2 effect Gingivitis 4 2 2 improvement

As can be seen from Table 14, the preparations having composition ofExamples of the present invention can have excellent efficacy byfacilitating delivery of a medicinal ingredient and securing sufficientattachment time.

INDUSTRIAL APPLICABILITY

The present invention can be provided as an oral preparation which canbe attached to teeth or tooth peripheries and the deliver a medicinalingredient into the oral cavity. The preparation of the presentinvention is for attaching to teeth or tooth peripheries with excellentadhesive force.

1. A preparation for attaching to teeth or tooth peripheries, wherein the preparation comprises a slime hydrogel containing a synthetic silica or an alginate compound.
 2. The preparation for attaching to teeth or tooth peripheries of claim 1, wherein the synthetic silica is at least one selected from silica powder, fumed silica, precipitated silica, colloidal silica, aerogel and silica sol.
 3. The preparation for attaching to teeth or tooth peripheries of claim 1, wherein the alginate compound is calcium alginate, potassium alginate, sodium alginate, triethanolamine alginate or a mixture thereof.
 4. The preparation for attaching to teeth or tooth peripheries of claim 1, wherein the alginate compound is contained in an amount of 0.1 wt % to 20 wt % based on the total weight of the preparation.
 5. The preparation for attaching to teeth or tooth peripheries of claim 1, wherein the hydrogel comprises polyvinyl alcohol (PVA) and a salt forming cross-links with —OH groups of the polyvinyl alcohol.
 6. The preparation for attaching to teeth or tooth peripheries of claim 5, wherein the salt forming cross-links with —OH groups of the polyvinyl alcohol is borate, phosphate or a mixture thereof.
 7. The preparation for attaching to teeth or tooth peripheries of claim 1, which comprises a medicinal ingredient for intra-oral delivery.
 8. The preparation for attaching to teeth or tooth peripheries of claim 7, wherein the medicinal ingredient is sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B 12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, titrated extract of Zea Mays L. unsaponifiable fraction, Magnoliae Cortex extract, Myrrha, Rhatany, Chamomile, policresulen, titrated extract of Centella Asiatica, nutmeg extract, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate or a mixture thereof.
 9. A preparation for attaching to teeth or tooth peripheries, which comprises a medicinal ingredient, a phase transition compound, a polymer that is water-insoluble but ethanol-soluble, and ethanol as a solvent, wherein the preparation is applied in liquid to teeth or tooth peripheries, and phase transited by saliva in the oral cavity, thereby having adhesiveness to teeth or tooth peripheries.
 10. The preparation for attaching to teeth or tooth peripheries of claim 9, wherein the phase transition compound is selected from glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate or a mixture thereof.
 11. The preparation for attaching to teeth or tooth peripheries of claim 9, wherein the phase transition compound is contained in an amount of 5 wt % to 80 wt % based on the total weight of the preparation.
 12. The preparation for attaching to teeth or tooth peripheries of claim 9, wherein the polymer that is water-insoluble but ethanol-soluble is ethyl cellulose, butyl ester of PVM/MA copolymer, polyvinyl acetate, polyvinyl acetate-phthalate, shellac, rosin, methacrylic acid copolymer or a mixture thereof.
 13. A preparation for attaching to teeth or tooth peripheries of claim 9, which has viscosity of 10,000 cPs or less before being in contact with water, but has phase transited to gel or solid having adhesiveness to teeth or oral tissues after being applied to teeth or oral cavity.
 14. The preparation for attaching to teeth or tooth peripheries of claim 13, which comprises the polymer that is water-insoluble but ethanol-soluble and the phase transition compound.
 15. The preparation for attaching to teeth or tooth peripheries of claim 13, which comprises both of: a polymer selected from glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate or a mixture thereof; and a polymer selected from ethyl cellulose, butyl ester of PVM/MA copolymer, polyvinyl acetate, polyvinyl acetate-phthalate, shellac, rosin, methacrylic acid copolymer or a mixture thereof.
 16. The preparation for attaching to teeth or tooth peripheries of claim 9, wherein the medicinal ingredient is sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, titrated extract of Zea Mays L. unsaponifiable fraction, Magnoliae Cortex extract, Myrrha, Rhatany, Chamomile, policresulen, titrated extract of Centella Asiatica, nutmeg extract, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate or a mixture thereof. 